CN1571817A - Ph responsive biodegradable polylactic acid derivatives forming polymeric micelles and uses thereof for poorly water soluble drug delivery - Google Patents
Ph responsive biodegradable polylactic acid derivatives forming polymeric micelles and uses thereof for poorly water soluble drug delivery Download PDFInfo
- Publication number
- CN1571817A CN1571817A CNA028206185A CN02820618A CN1571817A CN 1571817 A CN1571817 A CN 1571817A CN A028206185 A CNA028206185 A CN A028206185A CN 02820618 A CN02820618 A CN 02820618A CN 1571817 A CN1571817 A CN 1571817A
- Authority
- CN
- China
- Prior art keywords
- polylactic acid
- acid derivative
- aqueous solution
- lactic acid
- derivative
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229920000747 poly(lactic acid) Polymers 0.000 title claims abstract description 214
- 239000004626 polylactic acid Substances 0.000 title claims abstract description 162
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 239000000693 micelle Substances 0.000 title claims abstract description 29
- 238000012377 drug delivery Methods 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 91
- 239000007864 aqueous solution Substances 0.000 claims abstract description 49
- 229940079593 drug Drugs 0.000 claims abstract description 41
- -1 poly(lactic acid) Polymers 0.000 claims description 123
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 82
- 229920000642 polymer Polymers 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 239000012153 distilled water Substances 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- 230000006837 decompression Effects 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 238000001556 precipitation Methods 0.000 claims description 12
- 125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 238000006068 polycondensation reaction Methods 0.000 claims description 9
- 239000011734 sodium Chemical group 0.000 claims description 9
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 8
- 235000017550 sodium carbonate Nutrition 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 239000000178 monomer Substances 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- 229960002510 mandelic acid Drugs 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012346 acetyl chloride Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 229910052744 lithium Chemical group 0.000 claims description 5
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- 239000011591 potassium Chemical group 0.000 claims description 5
- CLWAXFZCVYJLLM-UHFFFAOYSA-N 1-chlorohexadecane Chemical compound CCCCCCCCCCCCCCCCCl CLWAXFZCVYJLLM-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 235000015320 potassium carbonate Nutrition 0.000 claims description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 3
- IPIVAXLHTVNRBS-UHFFFAOYSA-N decanoyl chloride Chemical compound CCCCCCCCCC(Cl)=O IPIVAXLHTVNRBS-UHFFFAOYSA-N 0.000 claims description 3
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- 239000000284 extract Substances 0.000 claims 2
- 238000012643 polycondensation polymerization Methods 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract description 36
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
- 159000000000 sodium salts Chemical class 0.000 description 30
- 229920001577 copolymer Polymers 0.000 description 22
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- 239000000126 substance Substances 0.000 description 20
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 20
- 239000000047 product Substances 0.000 description 15
- 229930105110 Cyclosporin A Natural products 0.000 description 13
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 13
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- 238000001914 filtration Methods 0.000 description 7
- 210000000813 small intestine Anatomy 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000002296 dynamic light scattering Methods 0.000 description 6
- 150000002431 hydrogen Chemical group 0.000 description 6
- 239000000463 material Substances 0.000 description 6
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- 238000001542 size-exclusion chromatography Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 125000004423 acyloxy group Chemical group 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 5
- 229910021645 metal ion Inorganic materials 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
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- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 4
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- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
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- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
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- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 235000005282 vitamin D3 Nutrition 0.000 description 1
- 239000011647 vitamin D3 Substances 0.000 description 1
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 1
- 229940021056 vitamin d3 Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/78—Preparation processes
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
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Abstract
Polylactic acid derivatives capable of forming micelles in an aqueous solution with a pH of 4 or above, having one terminal carboxyl group. The polylactic acid derivatives may be applied as a drug delivery system in various forms since poorly water soluble drugs can be entrapped inside the micelles.
Description
Technical field
The present invention relates to can pH be 4 or the higher aqueous solution in form micella and have the polylactic acid derivative of an end carboxyl and more specifically, the present invention relates to contain the polymer micelle composition of polylactic acid derivative.
Background of invention
For the drug delivery by oral or administered parenterally, the solubilising of poorly water soluble drugs is important.To the solubilising of poorly water soluble drugs, have several ordinary methods.For example, poorly water soluble drugs can be dissolved in the mixture with miscible organic solvent of water and water.Perhaps, with poorly water soluble drugs by its acid or alkali through its salt form of structurally-modified one-tenth, can increase the water-soluble of medicine.Other method comprises the complexing of poorly water soluble drugs and the third material or poorly water soluble drugs is rolled in the micella of tensio-active agent formation.Referring to Leon Lachman, " The theory and practice of industrialpharmacy ", Lea ﹠amp; Febiger, Philadelphia, 1986.
In the middle of aforesaid method, can will manufacture several nanometers by the micella that uses tensio-active agent to form to several microns size with can be dispersed in the aqueous solution subtly.Therefore, for the solubilising of poorly water soluble drugs, preferably use micella.
Tensio-active agent has the chemical structure that comprises hydrophilic block and hydrophobic block, and wherein hydrophilic block has high avidity in a side to glassware for drinking water, and at opposite side oil is had high avidity.If hydrophilic block occupies the majority, then tensio-active agent dissolves in water better and is opposite, if hydrophobic block occupies the majority, then tensio-active agent dissolves in organic solvent better.Tensio-active agent is divided into ion and nonionogenic tenside.In the solubilizing method of poorly water soluble drugs, nonionogenic tenside is owing to its electric neutrality, so do not influence poorly water soluble drugs by ionic interaction.This tensio-active agent comprises anion salt, sorbitan derivatives such as the Tween of derivative of fatty acid or polyglycol ether derivative and polyoxyethylated castor oil derivative such as Cremophor or the like of Span, polyoxyethylene monoalkyl ethers derivative (BRIJ and MYRJ series) and lipid acid.
EP0645145 has disclosed a kind of method, wherein uses Cremophor EL (a kind of nonionogenic tenside), solubilising taxol, a kind of medicine of poorly water soluble.Yet when oral or administered parenterally, this medicine of using surface active agent solubilization is owing to disadvantageous side effect, the application that causes having limitation as anaphylaxis.The shortcoming that it also has is that when long-time storage, because the micellar stability in the aqueous solution is very low, so medicine is separated from micella.
Reported to use by two-or the polymer micelle solubilising dewatering medicament made of three-segmented copolymer, wherein said multipolymer comprises hydrophilic polymer and hydrophobic biodegradable polymkeric substance such as the fatty acid polyester or the polyamino acid of polylalkylene glycol derivatives.For example, U.S. Patent No. 5449513 has disclosed a kind of Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock, and it comprises polyoxyethylene glycol as hydrophilic polymer, and polyamino acid derivative, and for example poly-benzyl aspartic acid etc. are as hydrophobic polymer.But the hydrophobic cancer therapy drug reagent of this Synthetic rubber, isoprene-styrene, hydrogenated, block, diblock solubilising, for example Zorubicin or anti-inflammatory agent such as indomethacin.Yet shortcoming is polyamino acid derivative not hydrolysis and cause non-required side effect in vivo.
In addition, that U.S. Patent No. 5429826 has disclosed is a kind of two-or many-segmented copolymer, it comprises hydrophilic polyalkylene glycol and hydrophobic poly(lactic acid).Particularly, above-mentioned patent disclosure have two of vinylformic acid end group by in the aqueous solution, making-or many-block copolymer micelleization, crosslinked then this micella.Although this method can be improved the stability of polymer micelle, shortcoming is that cross-linked polymer is not degraded, and and then can not use in vivo in use.
Adopted poly(lactic acid), be used for various forms of drug delivery systems, this is because it has good biocompatibility and biological degradability.Depend on its molecular weight, poly(lactic acid) has various performances, and at various prescriptions, as obtaining exploitation in microballoon, nano particle, polymer gel and the migration agent etc.Yet molecular weight does not dissolve in the aqueous solution greater than 2000 daltonian poly(lactic acid).Still not report is not successfully developed molecular weight and is lower than 2000 daltonian poly(lactic acid) as the drug delivery system, this be because they pH be 4 or the higher aqueous solution in soluble.
In view of foregoing problems, the improved polymer micelle composition of exploitation dewatering medicament transmission usefulness, but said composition physiologically acceptable and biodegradable will be paid attention to and be required.The invention provides this improved polymer micelle composition, but its physiologically acceptable and biodegradable and it can transmit dewatering medicament effectively, do not reduce its stability simultaneously.
Summary of the invention
The present invention relates to can pH be 4 or the higher aqueous solution in form the micellar polylactic acid derivative, it can be rolled in poorly water soluble drugs in the above-mentioned micella, but and and then solubilising poorly water soluble drugs.More specifically, the molecular weight of polylactic acid derivative of the present invention is that 500-2000 dalton and it can prepare by polycondensation 2-alpha-hydroxy carboxylic acid derivatives.
The present invention further provides the preparation method of polylactic acid derivative, described polylactic acid derivative is by under the situation that does not have catalyzer, and at high temperature, under the decompression, polycondensation 2-alpha-hydroxy carboxylic acid derivatives obtains simultaneously.
The present invention still further provides and contains the micellar polymer composition that is formed by polylactic acid derivative.
The present invention still further provides a kind of pharmaceutical composition, wherein poorly water soluble drugs be rolled in when pH be 4 or the micella that forms by polylactic acid derivative when higher in.
Polylactic acid derivative of the present invention is represented with molecular formula (I):
RO-CHZ-[A]
n-[B]
m-COOM??????(I)
Wherein A is-COO-CHZ; B is-COO-CHY ,-COO-CH
2CH
2CH
2CH
2CH
2-or-COO-CH
2CH
2OCH
2-; R is hydrogen, ethanoyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl; Z and Y are hydrogen, methyl or phenyl; M is hydrogen, sodium, potassium or lithium; N is the integer of 1-30; With m be the integer of 0-20.
Polylactic acid derivative of the present invention pH be 4 or the higher aqueous solution in can form micella.Formed micellar is of a size of 10-21nm and therefore is suitable as the carrier of poorly water soluble drugs.After this, will explain the present invention in more detail.
Brief description of drawings
Fig. 1 shows D of the present invention, the L-poly(lactic acid)
1The H-NMR spectrogram.
Fig. 2 shows D of the present invention, L-poly(lactic acid) sodium salt
1The H-NMR spectrogram.
Fig. 3 shows D of the present invention, size exclusion chromatography (SEC) figure of L-poly(lactic acid) sodium salt.In Fig. 3, be show to form micellar D (a), the peak of L-poly(lactic acid) sodium salt and (b) be to show not form micellar D the peak of L-poly(lactic acid) sodium salt.
Fig. 4 shows D, and the mixture of L-poly(lactic acid) sodium salt and taxol is at CDCl
3In the solvent
1The H-NMR spectrogram.
Fig. 5 shows D, and the mixture of L-poly(lactic acid) sodium salt and taxol is at D
2In the O solvent
1The H-NMR spectrogram.
Fig. 6 shows the chart of the solubilising of Cyclosporin A with the pH variation.
Fig. 7 shows D, the chart that the solubleness of L-poly(lactic acid) sodium salt changes with pH.
Before disclosing and describing polymer composition method of the present invention and use and manufacture method, be to be understood that, the present invention is not restricted on specific structure, processing step and the material that discloses in this place, because this kind structure, processing step and material can change sometimes. Scope of the present invention it is also understood that term as used herein only is used for describing the purpose of particular implementation scheme, and is not intended as restriction, because will only limit by appended claim and equivalent thereof.
Must be noted that employed singulative " (a, an) ", " should (the) " comprise a plurality of objects in this specification and appended claim, unless context has clearly explanation in addition. Therefore, for example, mention that the polymer that contains " end group " comprises two or more this kind groups, and mention that " a kind of hydrophobic medicine " comprises the medicine that two or more are such.
Describe and claimed the present invention in, will use following term according to the following definition of listing.
Term as used herein " biologically active agent " or " medicine " or any other similar term refer to be adapted to pass through the in advance known method in this area and/or come administration and induce required biological or pharmaceutically-active any chemistry or biological material or compound by the method that the present invention instructs. This kind effect can comprise, but being not limited to (1) has the prevention effect to organism and prevents that non-required biology effect is such as anti-infection, (2) relax the situation that causes because of disease, for example relax the pain or the inflammation that cause because of disease, and/or the disease of organism is relaxed, reduced or eliminate fully in (3). This kind effect can be local, and local anesthetic effect for example is provided, and perhaps can be whole body.
Term as used herein " but biodegradation " or " biodegradation " are defined as by solubilising and are hydrolyzed, or the effect by the biological material (it can be other product of enzyme or organism) that forms, make material change into so not complicated intermediate or final product.
Term as used herein " biological compatible " refers to material or by the solubilising hydrolysis, or the intermediate of this material of forming of the effect by the biological material (it can be other product of enzyme or organism and health not caused any side effect) that forms or final product.
" PLA " or " PLA " should refer to be derived from the polymer of the ring-opening polymerisation of lactic acid condensation or lactide. " poly-(second friendship ester) " or " PGA " should refer to be derived from the glycolic condensation or second is handed over the polymer of the ring-opening polymerisation of ester. " effectively amount " as used herein refer to the rational danger that in any medical treatment treatment, will take into account/benefit than under, the consumption that is enough to provide the biologically active agent of required part or whole body effect and performance.
" administration/use " as used herein and similar terms refer to transmit composition to the individuality that is treated, so that composition can the whole body circulation. Preferably, by subcutaneous, intramuscular, through skin, oral, route is used composition of the present invention in mucous membrane, blood vessel or in the abdominal cavity. Can be with the form of routine, perhaps as liquid solution or suspension, or before injection, be suitable in liquid solid form as the preparation of solution or suspension, or as emulsion, prepare the injection agent of this kind purposes. The appropriate excipients that can be used for administration comprises such as water, silane, sucrose, glycerine and ethanol etc.; Optionally, auxiliary substance such as wetting agent or emulsifying agent and the buffer solution etc. of trace. As for oral administration, it can be mixed with various forms, such as solution, tablet, capsule etc.
Refer now to the embodiment that exemplifies and describe it herein with specific language. However, be to be understood that and do not plan to limit the scope of the invention. The change of feature of the present invention described herein and further modification, and extra application and the principle of the present invention described herein, be considered within the scope of the invention, this can expect the technical staff who is familiar with relevant field and has a disclosure of invention.
The present invention relates to can pH be 4 or the higher aqueous solution in form the micellar polylactic acid derivative, it is rolled in poorly water soluble drugs in the above-mentioned micella, and then the medicine of solubilising poorly water soluble.More particularly, the present invention relates to the polylactic acid derivative shown in the molecular formula (I):
RO-CHZ-[A]
n-[B]
m-COOM????(I)
Wherein A is-COO-CHZ; B is-COO-CHY ,-COO-CH
2CH
2CH
2CH
2CH
2-or-COO-CH
2CH
2OCH
2-; R is hydrogen, ethanoyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl; Z and Y are hydrogen, methyl or phenyl; M is hydrogen, sodium, potassium or lithium; N is the integer of 1-30; With m be the integer of 0-20.
Polylactic acid derivative shown in the molecular formula (I) is the single polymers or the random copolymers of 2-alpha-hydroxy carboxylic acid derivatives preferably.More preferably polylactic acid derivative is to be selected from D, L-poly(lactic acid), D, the multipolymer of L-lactic acid and amygdalic acid, D, the multipolymer of L-lactic acid and oxyacetic acid, D, the multipolymer of L-lactic acid and caprolactone and D, L-lactic acid and 1, a kind of in 4-diox-2-ketone.
One end of polylactic acid derivative of the present invention can be carboxyl or its an alkali metal salt, preferred as alkali salt.An alkali metal salt forms the polylactic acid derivative of metal ion salt form, when ion is a univalent ion, for example when sodium, potassium or lithium.Polylactic acid derivative of the present invention is a solid at room temperature, and when in air, being exposed to moisture, because its neutral pH, so highly stable.
The other end of polylactic acid derivative of the present invention can be a hydroxyl, the available a kind of esterification that is selected from ethanoyl, benzoyl, decanoyl and the palmitoyl etc., or available methyl, ethyl or its group baseization of equal value.
Polylactic acid derivative of the present invention may be dissolved in the aqueous solution, and wherein hydrophilic the and hydrophobic components balance of polylactic acid derivative becomes polymer micelle.Therefore, if hydrophobic ester partly has too big molecular weight, the end carboxyl anion can not connect, and therefore is difficult to form micella.The number-average molecular weight of polylactic acid derivative of the present invention is preferably in 500-2000 dalton scope.If molecular weight is less than 500, then polymkeric substance is dissolved in the water fully, therefore can not form micella and if molecular weight greater than 2000, then hydrophobicity is too strong, so that can not form micella.Can be by in preparation method's process, control reaction temperature, vacuum tightness and time are waited the molecular weight of regulating polylactic acid derivative.
According to following experiment of the present invention, the solubleness of the polylactic acid derivative of molecular formula (I) changes with the variation of environment pH.PH be 4 or the higher aqueous solution in, polylactic acid derivative of the present invention dissolves fully, this causes solution transparent concerning naked eyes.Yet, if the pH of regulator solution is 4 or lower, the polylactic acid derivative partly precipitated, as shown in Figure 7.Can in being the 1-10 scope, use pH polylactic acid derivative of the present invention and preferred preparation and use it in the pH of 4-8 scope.
PH be 4 or the higher aqueous solution in disperse polylactic acid derivative of the present invention, and form micella.Identify that by size exclusion chromatography (SEC) formed micella and micellar gravel size decision are in about 9-21nm scope.Shown in Fig. 3 and table 6, proved that formed micell weight increases along with the increase of polylactic acid derivative concentration.Show that also formed micell weight increases when when replacing hydrophobicity that terminal hydroxy group causes the end group part with decanoyl or palmitoyl and increase.
The present invention relates to the preparation method of the polylactic acid derivative shown in the molecular formula (I) on the other hand.For example, the invention provides the preparation method of the polylactic acid derivative shown in the molecular formula (I) that R wherein is a hydrogen and wherein R be the preparation method of the polylactic acid derivative of ethanoyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl.
Wherein R is that the preparation method of polylactic acid derivative of the molecular formula (I) of hydrogen comprises step:
1) under high temperature and decompression, makes the monomer polycondensation of polylactic acid derivative;
2) in the product of step 1), add distilled water, the precipitation polylactic acid derivative, and and then remove low-molecular-weight prepolymer;
3) polylactic acid derivative is joined in neutrality or the alkaline aqueous solution, make the polylactic acid derivative dissolving;
4) from the solution of step 3), separate polylactic acid derivative; With
5) an alkali metal salt is joined in the polylactic acid derivative of step 4) acquisition, obtaining wherein, R is the polylactic acid derivative of the molecular formula (I) of hydrogen.
In aforesaid method, can save step 5).When saving step 5), be formed on the polylactic acid derivative that its end group contains not the carboxyl that is replaced by metal ion.
More specifically, in step 1, by under the situation that does not have catalyzer, under the decompression of 100-200 ℃ and 25-0.1mmHg, polycondensation 2-alpha-hydroxy carboxylic acid derivatives 6-24 hour.Shown in following embodiment, in step 1, the number-average molecular weight of gained polylactic acid derivative and productive rate change with the variation in temperature, reduced pressure and reaction times.By regulating these conditions, can obtain most preferred polylactic acid derivative.More specifically, temperature of reaction is high more, and the reaction times is long more, or reaction pressure is low more, and then the number-average molecular weight of polylactic acid derivative and productive rate are high more.
In step 2, distilled water is joined in the polylactic acid derivative that step 1 obtains, the precipitation polylactic acid derivative, and and then remove water-soluble low molecular weight prepolymer.
In step 3, it is 7 or higher that sedimentary polylactic acid derivative is dissolved in pH, and preferred pH is in the neutrality or alkaline aqueous solution of 7-9.
In step 4, by with the pH of the aqueous solution of the sour regulating step 3 of 1N to 1.5-2.5, separate polylactic acid derivative.Perhaps, add organic solvent such as methylene dichloride and chloroform etc. in the aqueous solution of the polylactic acid derivative that step 3 obtains, the polylactic acid derivative of extraction polylactic acid derivative and dry extraction obtains to contain the polylactic acid derivative of holding carboxyl.Contain hold carboxyl polylactic acid derivative preferably number-average molecular weight be the daltonian polymkeric substance of 500-2000.
In addition, in step 5, the polylactic acid derivative that obtains in the step 4 can be dissolved in acetone or the aqueous acetone solution.Then by adding the aqueous solution of sodium bicarbonate, yellow soda ash, saleratus, salt of wormwood or Quilonum Retard, in coming and gained solution.Evaporating solvent then, this causes with the wherein R that the metal ion salt form exists is the polylactic acid derivative of the molecular formula (I) of hydrogen.
The polylactic acid derivative that contains an end carboxyl at room temperature is that heavy-gravity liquid and the polylactic acid derivative that contains end group carboxylic acid metal ion salt at room temperature are solid.
Wherein R is that the preparation method of formula (I) polylactic acid derivative of ethanoyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl comprises step:
1) under high temperature and decompression, makes the monomer polycondensation of polylactic acid derivative;
2) in the product of step 1), add distilled water, the precipitation polylactic acid derivative, and and then remove low-molecular-weight prepolymer;
3) polylactic acid derivative is joined in neutrality or the alkaline aqueous solution, make the polylactic acid derivative dissolving;
4) from the solution of step 3), separate polylactic acid derivative; With
5) polylactic acid derivative and diacetyl oxide, Acetyl Chloride 98Min., Benzoyl chloride, decanoyl chloride, palmityl chloride, methyl-iodide or the iodoethane reaction that step 4) is obtained is to replace terminal hydroxy group; With
6) an alkali metal salt is joined in the polylactic acid derivative of replacement, obtaining wherein, R is the polylactic acid derivative of the molecular formula (I) of ethanoyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl.
In aforesaid method, can save step 6).When saving step 6), be formed on the polylactic acid derivative that its end group contains not the carboxyl that is replaced by metal ion.
In step 5); contain polylactic acid derivative and diacetyl oxide, Acetyl Chloride 98Min., Benzoyl chloride, decanoyl chloride, palmityl chloride, methyl-iodide or the iodoethane reaction of holding carboxyl; so that with esterified derivative such as ethanoyl, benzoyl, decanoyl, palmitoyl, or alkanisation derivative such as methyl or ethyl replace terminal hydroxy group.
The present invention also comprises polymer composition, and it contains the micella that is formed by polylactic acid derivative.The present invention also comprises pharmaceutical composition, it contain as pH be 4 or the micella that forms by polylactic acid derivative when higher in the poorly water soluble drugs that wraps up.
As for medicine oral or the parenteral administration poorly water soluble, pH be 4 or the higher aqueous solution in form and contain the micella of polylactic acid derivative of the present invention and the medicine of poorly water soluble is rolled in the micella, and and then solubilising.Shown in following embodiment, when using the medicine of poorly water soluble in vivo, contain the micella disintegration of polylactic acid derivative, thereby slowly discharge the medicine of poorly water soluble and demonstrate its drug effect.
The poorly water soluble drugs that can use polylactic acid derivative solubilising of the present invention is any medicine, as long as its water-solubleness is 10mg/ml or lower.Typical poorly water soluble drugs comprises taxol, KETOKONAZOL, itraconazole, Cyclosporin A, cisapride, paracetamol, acetylsalicylic acid, acetylsalicylic acid, indomethacin, the anti-general acid of methoxy, warfarin, Papaverine, benzothiazole (thioabenazole), miconazole, trifluoperazine, Zorubicin, omeprazole, Vitamin D3 500,000 I.U/GM, melphalan, nifedipine, digoxin, the phenylformic acid tryptophane, tyrosine, phenylalanine, aztreonam, Ibuprofen BP/EP, phenoxymethyl penicillin, Thalidomide, methyltestosterone, prochlorperazine, hydrocortisone, two deoxidation purine nucleoside, vitamins D
2White streptocide, the sulfo group urea, para-amino benzoic acid, melatonin, benzylpenicillin, Chlorambucil, diaza , digitoxin, the hydrocortisone butyrates, the metronidazole benzoate, tolbutamide, prostaglandin(PG), fluohydrocortisone, grisovin, miconazole nitrate, leukotriene B 4 inhibitors, Proprasylyte, theophylline, Flurbiprofen, Sodium Benzoate, phenylformic acid, riboflavin, benzodiazepine , phenylethyl barbituric acid, Glyburide, Sulphadiazine Sodium (sulphiazine), sulfaethylthiadiazole, diclofenac sodium, Phenytoin Sodium Salt, hydrochloric acid hioridazine, Bropirimine, hydrochlorothiazide and fluconazole etc.
The medicine of poorly water soluble also comprises microbiotic, anti-inflammatory analgesic agent, narcotic, hormone, hypertension drug, diabetes medicament, antiviral agent, Parkinson's disease medicine, presenile dementia medicine, antiemetic, immunosuppressive drug, medicine for ulcer, constipation medicine or anti-malarial agents except the above medicine of enumerating.
Preferably, the medicine that contains micelle composition of the present invention comprises that consumption is the medicine of poorly water soluble of 0.1-20.0wt% and the polylactic acid derivative of 80.0-99.9wt%.Can be with the micelle form that contains poorly water soluble drugs oral or parenteral administration polylactic acid derivative.
Administered parenterally is meant at polylactic acid derivative with after poorly water soluble drugs mixes, by means of the medicine of injection poorly water solubles such as blood vessel, subcutaneous lipids, muscle with more specifically by means of the medicine of subcutaneous lipids or intramuscular injection poorly water soluble.In addition, the prescription of oral administration comprises tablet or the capsule for preparing by the medicine that mixes polylactic acid derivative of the present invention and poorly water soluble.
In addition, as for administered parenterally, can prepare and in pH is the body fluid of 6-7, slowly form the micellar prescription.As for oral administration, can prepare in pH is the stomach of 1-2 and not discharge medicine, but in pH is the small intestine of 6-7 so that the micelle form of medicament solubilization discharges the prescription of medicine.
When oral administration, with the pharmaceutical composition of poorly water soluble drugs that contains of the present invention in stomach is transferred to small intestine.If pH is lower than the pH of small intestine in the stomach, then be included in the polylactic acid derivative in the pharmaceutical composition of the present invention, under low pH, keep tablet or capsule form, so medicine does not discharge.Yet if be when transferring to pharmaceutical composition in the small intestine under the 6-7 at pH, composition is with the slow solubilising of the micelle form that contains medicine, and discharges medicine and absorb in small intestine.The advantage of this performance is can be by preventing that its release has improved stability at unsettled medicine under the low pH under low pH, in addition, in the solution of pH1-2, precipitate, and and then have side effect as the medicine that causes stomach ulcer etc. such as anti-inflammatory analgesic agent etc., in stomach, do not discharge, but discharge in pH is the small intestine of 6-7, this can reduce side effect and improve its drug effect.
The invention still further relates to by using the polylactic acid derivative preparation to contain the micellar method of poorly water soluble drugs.
The medicine dissolution of polylactic acid derivative and poorly water soluble in acetone, vinyl acetic monomer, acetonitrile, methylene dichloride, ethanol, methyl alcohol, chloroform or acetic acid, is removed the uniform mixture of organic solvent and preparation polylactic acid derivative and poorly water soluble drugs.The pH that adds distilled water and regulate the aqueous solution is 4-8, and and then forms the micella that contains medicine automatically.Freeze-drying contains the micellar solution of poorly water soluble drugs then.
In addition, in order to prepare formula of oral, polylactic acid derivative and poorly water soluble drugs are dissolved in the organic solvent, remove organic solvent and polylactic acid derivative is mixed the production tablet with the mixture of poorly water soluble drugs with oral vehicle, or be filled in the capsule, produce capsule formula.
According to embodiments of the invention, the solubilising result of experiment of taxol and Cyclosporin A shows that the solubleness that micella is of a size of 14-35nm and medicine should be 10-25mg/ml, to guarantee the solubilising of medicine.
Following examples can make those skilled in the art more be expressly understood and how put into practice the present invention.Although should be appreciated that in conjunction with its preferred specific embodiments and described the present invention, these embodiments are subsequently intended setting forth, rather than limit the scope of the invention.Others of the present invention are conspicuous for the technician who belongs to field of the present invention.
Embodiment 1-12; Synthesizing of polylactic acid derivative
By under the situation that does not have catalyzer, polymerization 2-alpha-hydroxy carboxylic acid derivatives is 6-24 hour under high temperature (100-200 ℃) and decompression (100-0.1mmHg), follows purifying, thus the preparation polylactic acid derivative.
Embodiment 1:D, synthetic 1 of L-poly(lactic acid) (PLA-COOH)
L-lactic acid (100g) is introduced in the 250ml three neck round-bottomed flasks, and this flask is furnished with agitator.In 80 ℃ oil bath, in the heating flask, reacted 1 hour and use vacuum air pump, its pressure is dropped to 25mmHg, to remove excessive moisture.Under the decompression of 150 ℃ high temperature and 25mmHg, reacted 6 hours then, then termination reaction.In formed product, add 1 liter of distilled water, precipitation polymers.Sedimentary polymkeric substance is joined in the distilled water, thereby remove low-molecular-weight prepolymer, this prepolymer is 4 or when lower in the water soluble solution at pH.Then, sedimentary polymkeric substance being joined in 1 liter of distilled water, is 6-8 by the pH that dropwise adds the sodium bicarbonate adjusting aqueous solution.This moment, by centrifugal or filtering separation and remove water-insoluble polymkeric substance.By to wherein dropwise adding the 1N hydrochloric acid soln, the pH that regulates the aqueous solution is 2, precipitation polymers in the aqueous solution.With the sedimentary polymkeric substance of distilled water wash 2 times, separation and drying under reduced pressure, thereby obtain amorphous polymer (59g D, L-poly(lactic acid), productive rate: 59%).By means of
1The H-NMR spectrum, the number-average molecular weight of polymkeric substance is 540 dalton (Fig. 1).
Embodiment 2:D, the Synthetic 2 of L-poly(lactic acid) (PLA-COOH)
Obtain D according to the step identical with embodiment 1, the L-poly(lactic acid), different is that under the decompression of 160 ℃ high temperature and 10mmHg, reaction was carried out 12 hours, was 1140 daltonian D thereby obtain 66g (productive rate 66%) number-average molecular weight, the L-poly(lactic acid).
Embodiment 3:D, synthetic 3 of L-poly(lactic acid) (PLA-COOH)
Obtain D according to the step identical with embodiment 1, the L-poly(lactic acid), different is that under the decompression of 160 ℃ high temperature and 10mmHg, reaction was carried out 24 hours, was 1550 daltonian D thereby obtain 71g (productive rate 71%) number-average molecular weight, the L-poly(lactic acid).
Embodiment 4:D, synthetic 4 of L-poly(lactic acid) (PLA-COOH)
Obtain D according to the step identical with embodiment 1, the L-poly(lactic acid), different is that under the decompression of 160 ℃ high temperature and 5mmHg, reaction was carried out 24 hours, was 2100 daltonian D thereby obtain 75g (productive rate 75%) number-average molecular weight, the L-poly(lactic acid).
Synthetic D among the foregoing description 1-4 has been shown, the L-poly(lactic acid) in the following table 1.
Table 1
| Embodiment | Temperature (℃) | Time (hour) | Pressure (mmHg) | Mn (dalton) | Productive rate (%) |
| 1 | 150 | 6 | 25 | 540 | 59 |
| 2 | 160 | 12 | 10 | 1140 | 66 |
| 3 | 160 | 24 | 10 | 1550 | 71 |
| 4 | 160 | 24 | 5 | 2100 | 75 |
* productive rate=(polymkeric substance that is obtained/employed monomer) * 100
Embodiment 5:D, synthetic 1 of L-lactic acid and ethanol copolymer (PLGA-COOH)
With D, L-lactic acid (55g, 0.6mol) and oxyacetic acid (45g 0.6mol) is incorporated in the three neck round-bottomed flasks of 250ml together.Carry out the step identical with the foregoing description 1, different is that under the decompression of 150 ℃ high temperature and 10mmHg, reaction was carried out 12 hours, thereby obtaining 63g (productive rate 63%) number-average molecular weight is 920 daltonian D, L-lactic acid and ethanol copolymer (PLGA-COOH).D in products therefrom, the mol ratio of L-lactic acid/oxyacetic acid is 52/48.
Embodiment 6:D, the Synthetic 2 of L-lactic acid and ethanol copolymer (PLGA-COOH)
With D, L-lactic acid (73g, 0.8mol) and oxyacetic acid (27g 0.35mol) is incorporated in the three neck round-bottomed flasks of 250ml together.Carry out the step identical with the foregoing description 1, different is that under the decompression of 160 ℃ high temperature and 10mmHg, reaction was carried out 12 hours, thereby obtaining 65g (productive rate 65%) number-average molecular weight is 1040 daltonian D, L-lactic acid and ethanol copolymer (PLGA-COOH).D in products therefrom, the mol ratio of L-lactic acid/oxyacetic acid is 67/33.
Embodiment 7:D, synthetic 3 of L-lactic acid and ethanol copolymer (PLGA-COOH)
With D, L-lactic acid (91g, 1.0mol) and oxyacetic acid (9g 0.12mol) is incorporated in the three neck round-bottomed flasks of 250ml together.Carry out the step identical with the foregoing description 1, different is that under the decompression of 160 ℃ high temperature and 10mmHg, reaction was carried out 12 hours, thereby obtaining 68g (productive rate 68%) number-average molecular weight is 1180 daltonian D, L-lactic acid and ethanol copolymer (PLGA-COOH).D in products therefrom, the mol ratio of L-lactic acid/oxyacetic acid is 91/9.
Embodiment 8:D, synthetic 4 of L-lactic acid and ethanol copolymer (PLGA-COOH)
With D, L-lactic acid (73g, 0.8mol) and oxyacetic acid (27g 0.35mol) is incorporated in the three neck round-bottomed flasks of 250ml together.Carry out the step identical with the foregoing description 1, different is that under the decompression of 180 ℃ high temperature and 5mmHg, reaction was carried out 12 hours, thereby obtaining 73g (productive rate 73%) number-average molecular weight is 1650 daltonian D, L-lactic acid and ethanol copolymer (PLGA-COOH).D in products therefrom, the mol ratio of L-lactic acid/oxyacetic acid is 71/29.
Table 2 shows above embodiment 5-8 synthetic multipolymer.
Table 2
| Embodiment | The mol ratio of lactic acid and oxyacetic acid | Temperature of reaction (℃) | Reaction times (hour) | Pressure (mmHg) | Mn (dalton) | Productive rate (%) | |
| | Product | ||||||
| 5 | 50/50 | 52/48 | 150 | 12 | 10 | 920 | 63 |
| 6 | 70/30 | 67/33 | 160 | 12 | 10 | 1040 | 65 |
| 7 | 90/10 | 91/9 | 160 | 12 | 10 | 1180 | 68 |
| 8 | 70/30 | 71/29 | 180 | 24 | 5 | 1650 | 73 |
Embodiment 9; D, L-lactic acid and amygdalic acid multipolymer (PLMA-COOH) synthetic
With D, L-lactic acid (75g) and D, L-amygdalic acid (25g) are incorporated in the 250ml three neck round-bottomed flasks together, and this flask is furnished with agitator.In 80 ℃ oil bath, in the heating flask, reacted 1 hour and use vacuum air pump, its pressure is dropped to 25mmHg, to remove excessive moisture.Carry out the step identical with the foregoing description 1, different is that under the decompression of 180 ℃ high temperature and 10-20mmHg, reaction was carried out 12 hours, was 1750 daltonian D thereby obtain 54g (productive rate 54%) number-average molecular weight, L-lactic acid and amygdalic acid multipolymer.D in products therefrom, the mol ratio of L-lactic acid/amygdalic acid is 85/15.
Embodiment 10: acetoxyl group D, L-polylactic acid derivative (AcO-PLA-COOH) synthetic
With the above embodiment 2 synthetic D of 50g, L-poly(lactic acid) (Mn:1140 dalton) and 20ml Acetyl Chloride 98Min. are incorporated in the 250ml three neck round-bottomed flasks together.This flask is furnished with condenser and reaction mixture refluxed 4 hours under nitrogen gas stream.Remove excessive Acetyl Chloride 98Min. by distillation, then reaction product is joined in the mixture of ice and water.Slowly stir whole mixtures, with precipitation polymers.The polymkeric substance of precipitation separation, and use distilled water wash, be dissolved in the anhydrous propanone then.To wherein adding anhydrous magnesium sulfate, remove excessive moisture.Filter products therefrom, remove sal epsom.Use vacuum air pump to remove acetone, obtain highly viscous acetoxyl group D, L-poly(lactic acid) (46g, productive rate 92%).By means of
1H-NMR identifies that acetoxyl group is the unimodal of 2.02ppm.
Embodiment 11; Benzyloxy D, L-polylactic acid derivative (Benzoy10-PLA-COOH) synthetic
Carry out the step identical with above embodiment 10, different is to add Benzoyl chloride, rather than Mono Chloro Acetic Acid, thereby obtains 47g (productive rate: benzyloxy D 94%), L-poly(lactic acid).
Embodiment 12: palm acyloxy D, L-polylactic acid derivative (PalmO-PLA-COOH) synthetic
With the above embodiment 2 synthetic D of 20g, the L-poly(lactic acid) (Mn:1140 dalton) be incorporated in the 250ml round-bottomed flask.Under vacuum, in 120 ℃ oil bath, reactant is thoroughly dewatered.Cooling oil bath to 50 ℃, and to wherein adding 50ml acetone, all dissolve polymers.To its adding 5ml palmityl chloride with under 50 ℃ temperature, in nitrogen atmosphere, reacted 10 hours.With excessive hexane wash reaction product, to remove residual reactant.Remove hexane by distillation.Then, reaction product is dissolved in the acetone, and this solution is joined in the mixture of ice and water.Slowly stir whole mixtures, with precipitation polymers, isolating polymer is also used distilled water wash 2 times, is dissolved in the anhydrous propanone then.To wherein adding anhydrous magnesium sulfate, remove excessive moisture then.Filter products therefrom,, use vacuum air pump, remove acetone, thereby obtain palm acyloxy D, L-polylactic acid derivative (19.1g, productive rate: 96%) to remove sal epsom.By means of
1H-NMR identifies that ethanoyl is 0.88,1.3 and the peak of 2.38ppm.
Embodiment 13-22: the carboxylate salt of polylactic acid derivative synthetic
Above embodiment 1-12 synthetic polylactic acid derivative is dissolved in the acetone or its aqueous solution, with sodium bicarbonate, yellow soda ash, saleratus or salt of wormwood or their reactant aqueous solution, prepares their carboxylate salt then.
Embodiment 13; Synthetic 1 of poly(lactic acid) sodium salt (PLA-COONa)
With above embodiment 1 synthetic D, the L-poly(lactic acid) (Mn:540 dalton) be dissolved in the acetone.Be incorporated into this solution in the round-bottomed flask and this flask is furnished with agitator.At room temperature slowly stir this solution, and to wherein slowly adding sodium hydrogen carbonate solution (1N), neutralizing it, one is 7 until reaching pH.Take out acetone soln in a small amount, and in a large amount of distilled water, dilute, to measure the pH of solution.To wherein adding anhydrous magnesium sulfate, and therefrom remove the filtration moisture.Filter the gained mixture, and adopt solvent evaporation instrument evaporation acetone, thereby obtain white solid.This solid is dissolved in the anhydrous propanone, and filtering solution, to remove insoluble residue in anhydrous propanone.Evaporation acetone, thereby the poly(lactic acid) sodium salt (productive rate: 96%) of acquisition white solid.As shown in Figure 2, by means of
1H-NMR, observe the hydrogen peak adjacent with carboxyl at the 4.88ppm place and in water the pH of lysigenous polymkeric substance be 6.5-7.5.
Embodiment 14; The Synthetic 2 of poly(lactic acid) sodium salt (PLA-COONa)
(productive rate: 95%), different is to use above embodiment 2 synthetic D, L-poly(lactic acid) (Mn:1140 dalton) and aqueous sodium carbonate according to the step synthesizing polylactic acid sodium salt identical with above embodiment 13.
Embodiment 15: acetoxyl group-D, L-poly(lactic acid) sodium salt (AcO-PLA-COONa) synthetic
According to the step synthesis of acetyl oxygen base-D identical with above embodiment 13, (productive rate: 95%), different is to use above embodiment 10 synthetic D, L-poly(lactic acid) (Mn:1140 dalton) and aqueous sodium carbonate to L-poly(lactic acid) sodium salt.
Embodiment 16: palm acyloxy D, L-poly(lactic acid) sodium salt (PalmO-PLA-COONa) synthetic
With above embodiment 12 synthetic palm acyloxy D, L-poly(lactic acid) (Mn:1140 dalton) is dissolved in the aqueous solution (28.6v/v%) of acetone fully.Be incorporated into this solution in the round-bottomed flask and this flask is furnished with agitator.At room temperature slowly stir this solution, then to wherein adding sodium bicarbonate aqueous solution (1N), until the pH value is 7.To wherein adding anhydrous magnesium sulfate, remove excess humidity.Filter products therefrom, and adopt solvent evaporation instrument evaporation acetone solvent, thereby obtain white solid.This solid is dissolved in the anhydrous propanone, and filtering solution, to remove insoluble residue in anhydrous propanone.Evaporation acetone, thereby the palm acyloxy D of acquisition white solid, L-poly(lactic acid) sodium salt (productive rate: 96%).
Embodiment 17: poly(lactic acid) sylvite (PLA-COOK) synthetic
(productive rate: 98%), different is to use above embodiment 3 synthetic D, L-poly(lactic acid) (Mn:1550 dalton) and potassium bicarbonate aqueous solution according to the step synthesizing polylactic acid sodium salt identical with above embodiment 13.
Embodiment 18; Synthetic 3 of poly(lactic acid) sodium salt (PLA-COONa)
(productive rate: 95%), different is to use above embodiment 4 synthetic D, L-poly(lactic acid) (Mn:2100 dalton) according to the step synthesizing polylactic acid sodium salt identical with above embodiment 13.
Embodiment 19; D, synthetic 1 of the sodium salt of L-lactic acid and ethanol copolymer (PLGA-COONa)
According to the step synthetic D identical with above embodiment 13, the sodium salt of L-lactic acid and ethanol copolymer (productive rate: 98%), different is to use above embodiment 5 synthetic D, L-lactic acid and ethanol copolymer (Mn:920 dalton) and aqueous sodium carbonate.
Embodiment 20:D, the Synthetic 2 of the sodium salt of L-lactic acid and ethanol copolymer (PLGA-COONa)
According to the step synthetic D identical with above embodiment 13, the sodium salt of L-lactic acid and ethanol copolymer (productive rate: 93%), different is to use above embodiment 6 synthetic D, L-lactic acid and ethanol copolymer (Mn:1040 dalton) and aqueous sodium carbonate.
Embodiment 21:D, the sylvite of L-lactic acid and ethanol copolymer (PLGA-COOK) synthetic
According to the step synthetic D identical with above embodiment 13, the sylvite of L-lactic acid and ethanol copolymer (productive rate: 92%), different is to use above embodiment 7 synthetic D, L-lactic acid and ethanol copolymer (Mn:1180 dalton) and wet chemical.
Embodiment 22; D, synthetic 3 of the sodium salt of L-lactic acid and ethanol copolymer (PLGA-COONa)
According to the step synthetic D identical with above embodiment 13, (productive rate: 98%), different is to use above embodiment 8 synthetic D, L-lactic acid and ethanol copolymer (Mn:1650 dalton) to the sodium salt of L-lactic acid and ethanol copolymer.
Following table 3 shows carboxylic acid metal's ion salt of above embodiment 13-22 synthetic polylactic acid derivative.
Table 3
| Embodiment | Reactant (MW) | Alkali | Product | Mn (dalton) | Productive rate (%) |
| 13 | PLA-COOH (540) | NaHCO 3 | PLA-COONa | 540 | 96 |
| 14 | PLA-COOH (1140) | Na 2CO 3 | PLA-COONa | 1140 | 95 |
| 15 | AcO-PLA-COOH (1140) | Na 2CO 3 | AcO-PLA-COONa | 1140 | 95 |
| 16 | PalmO-PLA-COOH (1140) | NaHCO 3 | PalmO-PLA-COON a | 1140 | 96 |
| 17 | PLA-COOH (1550) | KHCO 3 | PLA-COOK | 1550 | 98 |
| 18 | PLA-COOH (2100) | NaHCO 3 | PLA-COONa | 2100 | 95 |
| 19 | PLGA-COOH (920) | Na 2CO 3 | PLGA-COONa | 920 | 98 |
| 20 | PLGA-COOH (1040) | NaHCO 3 | PLGA-COONa | 1040 | 93 |
| 21 | PLGA-COOH (1180) | K 2CO 3 | PLGA-COOK | 1180 | 92 |
| 22 | PLGA-COOH (1650) | NaHCO 3 | PLGA-COONa | 1650 | 98 |
EXPERIMENTAL EXAMPLE 1: depend on the micelle formation of pH
With D, L-poly(lactic acid) sodium salt (Mn:1000 dalton) is dissolved in the aqueous solution and the pH by regulator solution, estimates micellar and forms.Use DLS (dynamic light scattering, ZetaPlus, BrookhavenInstruments Corp.), measure the micellar granularity that forms.Fig. 7 and table 4 show the result.
Table 4
| pH | Micelle formation | Micellar mean particle size (nm) |
| 2 | X | - |
| 4 | 0 | 12 |
| 6 | 0 | 12 |
PH be 4 or the higher aqueous solution in the polymer formation micella, thereby become clear solution, but pH be 4 or lower situation under precipitate.
EXPERIMENTAL EXAMPLE 2; Depend on the micelle formation of M.W.
With number-average molecular weight is 200,500 and 700 daltonian each D, and the L-poly(lactic acid) is dissolved in the distilled water, and measures their solubleness and pH.Mw is 200 daltonian D, and the L-poly(lactic acid) forms transparent aqueous solution, but polymkeric substance precipitates in the L-poly(lactic acid) solution at 500 dalton or higher D.The pH of the above-mentioned aqueous solution is 1-2.Regulate the pH to 6.5-7.5 of the aqueous solution, make D, the L-poly(lactic acid) is dissolved fully.Use DLS (dynamic light scattering, ZetaPlus, Brookhaven Instruments Corp.), measure the micellar granularity that forms.Table 5 shows the result.
Table 5
| Mn (dalton) | Micellar mean particle size (nm) |
| 200 | Can't measure |
| 500 | 9.2 |
| 700 | 12 |
EXPERIMENTAL EXAMPLE 3: depend on the micelle formation of the concentration of polymkeric substance and kind
Above embodiment 1-22 synthetic polylactic acid derivative is dissolved in the distilled water.Then, prove whether form micella, and measure the micellar granularity that forms.The polylactic acid derivative of embodiment 1-12 is dissolved in the distilled water, and use sodium bicarbonate etc. is regulated those just dissolvings under the situation of not regulating pH of pH and embodiment 13-22, and this is because their original water solubles.After the dissolving polylactic acid derivative, the pH of solution is 6.5-7.5.Measure the solubleness of polylactic acid derivative, polymkeric substance is joined in the distilled water, and every interval was acutely shaken mixture in 5 minutes 30 seconds.(1g) is dissolved in the 10ml distilled water with polymkeric substance, and makes water solution flow cross the filtering membrane that the aperture is 200nm.Aqueous solutions of polymers clarification and transparent.Not have the fact of variation according to polymer concentration after filtering, prove that polylactic acid derivative is water-soluble easily.
In addition, with above-mentioned polymer dissolution be among 7.4 the PBS (salt solution of phosphate buffered) and use SEC (size exclusion chromatography, Water410 differential refractometer) prove whether form micella at pH.Moving phase is that the PBS and the flow velocity that contain NaCl (6g/ml) are 1ml/min.Fig. 3 and following table 6 show the micelle formation of the concentration that depends on employed polymkeric substance and kind.
Table 6: depend on the micelle formation of polymer concentration and kind
| Polymer concentration (mg/ml) | The area of micellization PLA-COONa (a) | The area (b) of free PLA-COONa | a/b |
| 6.25 | 60107 | 132913 | 0.45 |
| 12.5 | 154690 | 266794 | 0.58 |
| 25 | 355459 | 508965 | 0.70 |
| 50 | 797774 | 947810 | 0.84 |
| Polymer concentration (mg/ml) | The area of micellization PalmO-PLA-COONa (a) | The area (b) of free PalmO-PLA-COONa | a/b |
| 6.25 | 1735374 | 91192 | 19.03 |
| 12.5 | 3773480 | 157852 | 23.91 |
| 25 | 7836980 | 267143 | 29.34 |
| 50 | 16600792 | 537877 | 30.86 |
As shown in Figure 3, micellization polymer moieties (a) and dissolved polymers part (b) peak separately has been shown in spectrogram.In addition, as shown in table 6, show that the relative peak area of micellization polymer moieties increases.According to The above results, prove that formed micella content increases with polymer concentration.
In addition, use DLS (dynamic light scattering, ZetaPlus, Brookhaven InstrumentsCorp.), measure the micellar granularity that forms.The results are shown in Table 7.
Table 7: the micellar granularity that forms
| Embodiment | Mean particle size (nm) | The concentration of aqueous solutions of polymers (mg/ml) |
| 13 | 10 | 10 |
| 14 | 12 | 10 |
| 15 | 15 | 10 |
| 16 | 21 | 10 |
| 17 | 15 | 10 |
| 18 | 21 | 10 |
| 19 | 12 | 10 |
| 20 | 13 | 10 |
| 21 | 15 | 10 |
| 22 | 18 | 10 |
As shown in table 7, the micellar mean particle size that forms is 10-21nm.With the suitable dimension of polymer micelle be 100nm or lower, this makes hydrophilic outer shell because of polymer micelle cause the medicine minimum of catching because of RE system (RES) in vivo, and the hydrophilic outer shell of described polymer micelle systemic circulation for a long time.Inhibition is because due to the high molecular through renal excretion.Micella of the present invention not only has the suitable dimension that is fit to above-mentioned condition, and because the stability of the increase that its small size causes, so also have wide range of applications.
EXPERIMENTAL EXAMPLE 4: the solubilising test of poorly water soluble drugs
With the foregoing description synthetic D, the sodium salt of L-polylactic acid derivative and taxol are dissolved in organic solvent such as acetone, ethanol, vinyl acetic monomer, acetonitrile, methylene dichloride or the chloroform together, thereby obtain clear solution.Adopt the vacuum-evaporation instrument, from solution, remove organic solvent, obtain poorly water soluble drugs and D, the uniform mixture of the sodium salt of L-polylactic acid derivative.This mixture is dissolved in the aqueous solution that pH is 4-8.Make the formed micellar aqueous solution that contains poorly water soluble drugs flow through the filtering membrane that the aperture is 200nm, remove undissolved medicine.Then, by the drug level in the chromatogram quantitative analysis of the liquid phase aqueous solution.The results are shown in Table 8.
Table 8
| Polymkeric substance (MW) | Medicine | The ratio (%) of drug/polymer | Micella size (nm) | The solubleness of medicine (mg/ml) |
| PLA-COONa (1140) | | 5 | 14 | 25 |
| PLA-COONa (1140) | Taxol | 10 | 24 | 20 |
| PLA-COONa (1140) | Taxol | 15 | 30 | 15 |
| PLA-COOK (1550) | | 1 | 18 | 15 |
| PLGA-COONa (2100) | | 5 | 28 | 21 |
| PLGA-COONa (1040) | Cyclosporin A | 10 | 35 | 22 |
| PLGA-COONa (1040) | | 5 | 16 | 25 |
| PLGA-COOK (1180) | | 2 | 18 | 10 |
| PLGA-COONa (1650) | Taxol | 10 | 29 | 23 |
| PalmO-PLA-COONa (1140) | Taxol | 10 | 34 | 23 |
As above shown in the table 8, polylactic acid derivative of the present invention is solubilising poorly water soluble drugs such as taxol and Cyclosporin A effectively.The solubleness of taxol in water is 0.01mg/ml or lower, but uses polylactic acid derivative of the present invention, but solubilising is a large amount of, promptly the taxol that exists with micelle form of 15-25mg/ml and as a result high amount of drug can be administered in the body.
In addition, with taxol and D, the mixture of the sodium salt of L-polylactic acid derivative is dissolved in CDCl
3And D
2Among the O, carry out then
1H-NMR.Figure 4 and 5 show the result.As shown in Figure 4, poly(lactic acid) does not form micella, and this is because CDCl
3It is organic solvent.Therefore, demonstrate the characteristic peak of benzyloxy in the taxol at the 7.0-8.2ppm place.Yet, as shown in Figure 5, when it being dissolved in the D that taxol is had very little solubleness
2In the time of among the O, taxol is rolled in the micella of polylactic acid derivative and solubilising.Therefore, exist
1In the H-NMR spectrum, do not demonstrate the benzyloxy base peak at the 7.0-8.2ppm place.Obtain above result, be because taxol is surrounded by the micella of polylactic acid derivative, thereby form core, therefore not influenced by the nuclear-magnetism field of NMR.
The micellar preparation and evaluation that contain poorly water soluble drugs that EXPERIMENTAL EXAMPLE 5:pH-relies on
With the above embodiment 13 synthetic D of 900mg, the sodium salt of L-polylactic acid derivative and 100mg Cyclosporin A are dissolved in the 10ml acetone.Then, use the vacuum-evaporation instrument to remove acetone, obtain D, the homogeneous solid mixture of the sodium salt of L-polylactic acid derivative and Cyclosporin A.Use stamping machine compacting solid, the disk of preparation diameter 1cm and thickness 2mm.At pH is 2 times, and the disk that will contain Cyclosporin A joins in the 10ml hydrochloric acid soln and at 37 ℃ down in the insulation, measures the concentration of Cyclosporin A in the aqueous solution frequently.After 2 hours,, when being incubated under the same conditions then, measure the concentration of Cyclosporin A in the aqueous solution frequently to the pH to 6.2 that wherein adds the sodium bicarbonate and the adjusting aqueous solution.The results are shown in Table 6.
As shown in Figure 6, because polylactic acid derivative is 2 times not solubilisings at pH, so medicine does not discharge from the plate-like solid.After this, when pH became 2-6, the slow solubilising of polylactic acid derivative comprised medicine with micelle form simultaneously and medicine is discharged in the water gradually.In addition, when pH regulator is 6, about 80% medicine in 1 hour, be released and after 2 hours 100% medicine be released.
Above result shows, depends on pH, and polylactic acid derivative can be by being rolled in medicine in the micella that contains polylactic acid derivative, comes solubilize drugs and as time goes by, can measure solubleness after regulating pH.Under the oral administration situation of the prescription that contains poorly water soluble drugs and polylactic acid derivative, think that medicine can not discharge in stomach, solubilising and absorption in small intestine then.
Should be appreciated that above-described embodiment only is exemplifying of principle of the invention application.Many modifications be can under the situation that does not break away from spirit and scope of the invention, derive and can this modification and arrangement be intended covering for alternate embodiment and appended claim.Therefore, although the present invention shown in the drawings, and with thinking that at present the most realistic details relevant with embodiment preferred of the present invention at length fully described the present invention, but it is evident that those skilled in the art can make many modifications under the situation that does not break away from principle listed in the claim and notion.
Claims (19)
- An energy pH be 4 or the higher aqueous solution in form the micellar polylactic acid derivative, described polylactic acid derivative useful molecules formula (I) expression:RO-CHZ-[A] n-[B] m-COOM????(I)Wherein A is-COO-CHZ; B is-COO-CHY ,-COO-CH 2CH 2CH 2CH 2CH 2-or-COO-CH 2CH 2OCH 2-; R is hydrogen, ethanoyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl; Z and Y are hydrogen, methyl or phenyl; M is hydrogen, sodium, potassium or lithium; N is the integer of 1-30; With m be the integer of 0-20.
- 2. the polylactic acid derivative of claim 1, wherein the number-average molecular weight of polylactic acid derivative is 500-2000 dalton.
- 3. the polylactic acid derivative of claim 1, wherein polylactic acid derivative is selected from D, L-poly(lactic acid), D, the multipolymer of L-lactic acid and amygdalic acid, D, the multipolymer of L-lactic acid and oxyacetic acid, D, the multipolymer of L-lactic acid and caprolactone and D, L-lactic acid and 1, a kind of in 4-diox-2-ketone.
- 4. the polylactic acid derivative of claim 1, wherein M is sodium, potassium or lithium.
- 5. the polylactic acid derivative of claim 1, wherein R is decanoyl or palmitoyl.
- 6. polylactic acid derivative, it is by the method preparation that comprises the steps:1) under high temperature and decompression, makes the monomer polycondensation of polylactic acid derivative;2) in the product of step 1), add distilled water, the precipitation polylactic acid derivative, and and then remove low-molecular-weight prepolymer;3) polylactic acid derivative is joined in neutrality or the alkaline aqueous solution, make the polylactic acid derivative dissolving;4) from the solution of step 3), separate polylactic acid derivative; With5) an alkali metal salt is joined in the polylactic acid derivative of step 4) acquisition.
- 7. the polylactic acid derivative of claim 6, wherein in step 1, the temperature of reaction of condensation polymerization step is 100-200 ℃.
- 8. the polylactic acid derivative of claim 6 wherein under the pressure of 25-0.1mmHg, carries out the polycondensation of step 1.
- 9. the polylactic acid derivative of claim 6 wherein by acid is joined in the aqueous solution of step 3, and is regulated pH to 1.5-2.5, precipitation polylactic acid derivative, thereby the polylactic acid derivative in the separating step 4.
- 10. the polylactic acid derivative of claim 6 wherein by organic solvent being joined in the aqueous solution of step 3, extracts polylactic acid derivative, thus the polylactic acid derivative in the separating step 4.
- 11. the polylactic acid derivative of claim 6, wherein an alkali metal salt in the step 5 is selected from sodium bicarbonate, yellow soda ash, saleratus, salt of wormwood and Quilonum Retard.
- 12. wherein R is the polylactic acid derivative of the molecular formula (I) of ethanoyl, benzoyl, decanoyl, palmitoyl, methyl or ethyl, it is to be prepared by the method that comprises the steps:1) under high temperature and decompression, makes the monomer polycondensation of polylactic acid derivative;2) in the product of step 1), add distilled water, the precipitation polylactic acid derivative, and and then remove low-molecular-weight prepolymer;3) polylactic acid derivative is joined in neutrality or the alkaline aqueous solution, make the polylactic acid derivative dissolving;4) from the solution of step 3), separate polylactic acid derivative; With5) polylactic acid derivative and diacetyl oxide, Acetyl Chloride 98Min., Benzoyl chloride, decanoyl chloride, palmityl chloride, methyl-iodide or the iodoethane reaction that step 4) is obtained is to replace terminal hydroxy group; With6) an alkali metal salt is joined in the polylactic acid derivative of replacement.
- 13. the polylactic acid derivative of claim 12, wherein in step 1, the temperature of reaction of condensation polymerization step is 100-200 ℃.
- 14. the polylactic acid derivative of claim 12 wherein under the pressure of 25-0.1mmHg, carries out the polycondensation of step 1.
- 15. the polylactic acid derivative of claim 12 wherein by acid is joined in the aqueous solution of step 3, and is regulated pH to 1.5-2.5, the precipitation polylactic acid derivative, thus carry out the step of the polylactic acid derivative in the separating step 4.
- 16. the polylactic acid derivative of claim 12 wherein by organic solvent being joined in the aqueous solution of step 3, extracts polylactic acid derivative, thereby carries out the step of the polylactic acid derivative in the separating step 4.
- 17. the polylactic acid derivative of claim 12, wherein an alkali metal salt in the step 5 is selected from sodium bicarbonate, yellow soda ash, saleratus, salt of wormwood and Quilonum Retard.
- 18. a polymer composition that contains polymer micelle, this polymer micelle comprise any one polylactic acid derivative of claim 1-17.
- 19. a pharmaceutical composition, wherein poorly water soluble drugs is rolled in the polymer micelle, and described polymer micelle comprises any one polylactic acid derivative of claim 1-17.
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| KR2001/64164 | 2001-10-18 | ||
| KR20010064164 | 2001-10-18 |
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| CN1260294C CN1260294C (en) | 2006-06-21 |
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| EP (1) | EP1448710B1 (en) |
| JP (1) | JP2005505675A (en) |
| KR (1) | KR100517253B1 (en) |
| CN (1) | CN1260294C (en) |
| AT (1) | ATE358160T1 (en) |
| AU (1) | AU2002353551B2 (en) |
| CA (1) | CA2463517C (en) |
| DE (1) | DE60219194T2 (en) |
| ES (1) | ES2283623T3 (en) |
| HK (1) | HK1071390A1 (en) |
| MX (1) | MXPA04003513A (en) |
| NZ (1) | NZ532112A (en) |
| WO (1) | WO2003033593A1 (en) |
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| CN103269690A (en) * | 2010-12-24 | 2013-08-28 | 株式会社三养生物制药 | Sustained-release polymeric microparticles containing poorly water-oluble drug and method for preparing the same |
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| KR20050064075A (en) * | 2003-12-23 | 2005-06-29 | 주식회사 삼양사 | Pharmaceutical formulations for itraconazole |
| WO2005066238A1 (en) * | 2003-12-30 | 2005-07-21 | 3M Innovative Properties Company | Medicinal compositions and method for the preparation thereof |
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| KR101118199B1 (en) * | 2004-12-20 | 2012-03-15 | 주식회사 삼양홀딩스 | Polymeric micelle composition for solubilizing tacrolimus |
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| EP2229417B1 (en) * | 2007-12-31 | 2014-07-30 | Samyang Biopharmaceuticals Corporation | Process for the preparation of highly pure amphiphilic copolymer comprising hydrophobic block from alpha-hydroxy acid |
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| KR101224004B1 (en) * | 2009-12-29 | 2013-01-22 | 주식회사 삼양바이오팜 | A polymer for protein, polypeptide or peptide drug delivery and a method for preparing the same, and a composition for sustained release of protein, polypeptide or peptide drug and a method for preparing the same |
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- 2002-10-17 AU AU2002353551A patent/AU2002353551B2/en not_active Ceased
- 2002-10-17 JP JP2003536326A patent/JP2005505675A/en active Pending
- 2002-10-17 ES ES02788877T patent/ES2283623T3/en not_active Expired - Lifetime
- 2002-10-17 AT AT02788877T patent/ATE358160T1/en not_active IP Right Cessation
- 2002-10-17 EP EP02788877A patent/EP1448710B1/en not_active Expired - Lifetime
- 2002-10-17 US US10/492,091 patent/US8778322B2/en active Active
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103269690A (en) * | 2010-12-24 | 2013-08-28 | 株式会社三养生物制药 | Sustained-release polymeric microparticles containing poorly water-oluble drug and method for preparing the same |
| CN107412168A (en) * | 2010-12-24 | 2017-12-01 | 株式会社三养生物制药 | Release polymer particulate containing poorly water soluble drugs and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| DE60219194T2 (en) | 2008-01-03 |
| KR20030032896A (en) | 2003-04-26 |
| ATE358160T1 (en) | 2007-04-15 |
| HK1071390A1 (en) | 2005-07-15 |
| CA2463517C (en) | 2010-03-16 |
| ES2283623T3 (en) | 2007-11-01 |
| EP1448710B1 (en) | 2007-03-28 |
| MXPA04003513A (en) | 2004-07-23 |
| NZ532112A (en) | 2005-09-30 |
| CN1260294C (en) | 2006-06-21 |
| EP1448710A1 (en) | 2004-08-25 |
| AU2002353551B2 (en) | 2005-09-08 |
| CA2463517A1 (en) | 2003-04-24 |
| WO2003033593A1 (en) | 2003-04-24 |
| US8778322B2 (en) | 2014-07-15 |
| US20040247561A1 (en) | 2004-12-09 |
| DE60219194D1 (en) | 2007-05-10 |
| JP2005505675A (en) | 2005-02-24 |
| KR100517253B1 (en) | 2005-09-28 |
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